Beta-hydroxyphenylalkylamines and their use for treating glaucoma

ABSTRACT

β-hydroxyphenylalkylamines and their use for lowering and controlling ocular hypertension and treating glaucoma are disclosed.

BACKGROUND OF THE INVENTION

The present invention relates to various β-hydroxyphenylalkylamines.These compounds, some of which are novel, are useful for lowering andcontrolling normal or elevated intraocular pressure (IOP) and fortreating glaucoma.

The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. The several morphologically or functionally distinct typesof glaucoma are typically characterized by elevated IOP, which isconsidered to be causally related to the pathological course of thedisease. Ocular hypertension is a condition wherein intraocular pressureis elevated, but no apparent loss of visual function has occurred; suchpatients are considered to be at a high risk for the eventualdevelopment of the visual loss associated with glaucoma. If glaucoma orocular hypertension is detected early and treated promptly withmedications that effectively reduce elevated intraocular pressure, lossof visual function or its progressive deterioration can generally beameliorated. Drug therapies that have proven to be effective for thereduction of intraocular pressure include both agents that decreaseaqueous humor production and agents that increase the outflow facility.Such therapies are in general administered by one of two possibleroutes, topically (direct application to the eye) or orally.

There are some individuals who do not respond well when treated withcertain existing glaucoma therapies. There is, therefore, a need forother topical therapeutic agents that control IOP.

Serotonergic 5-HT_(1A) agonists have been reported as beingneuroprotective in animal models and many of these agents have beenevaluated for the treatment of acute stroke among other indications.This class of compounds has been mentioned for the treatment of glaucoma(lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.)and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol.210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT)(a 5-HT_(1A) agonist) reduces IOP in rabbits. Wang, et al. (Current EyeResearch, Vol. 16(8):769-775, August 1997, and IVOS, Vol. 39(4), S488,March, 1998) indicate that 5-methylurapidil, an α_(1A) antagonist and5-HT_(1A) agonist lowers IOP in the monkey, but due to its α_(1A)receptor activity. Also, 5-HT_(1A) antagonists are disclosed as beinguseful for the treatment of glaucoma (elevated IOP) (e.g., WO 92/0338,McLees). Furthermore, DeSai, et al. (WO 97/35579) and Macor, et al.(U.S. Pat. No. 5,578,612) relate to the use of 5-HT₁ and 5-HT_(1-like)agonists for the treatment of glaucoma (elevated IOP). Theseanti-migraine compounds are 5-HT_(1B,D,E,F) agonists, e.g., sumatriptanand naratriptan and related compounds.

It has been found that serotonergic compounds which possess agonistactivity at 5-HT₂ receptors effectively lower and control normal andelevated IOP and are useful for treating glaucoma, see pendingapplication, U.S. Ser. No. 09/787,332 (WO 00/16761), incorporated hereinby reference. Compounds that act as agonists at 5-HT₂ receptors are wellknown and have shown a variety of utilities, primarily for disorders orconditions associated with the central nervous system (CNS). U.S. Pat.No. 5,494,928 relates to certain 2-(indol-1-yl)-ethylamine derivativesthat are 5-HT_(2C) agonists for the treatment of obsessive compulsivedisorder and other CNS derived personality disorders. U.S. Pat. No.5,571,833 relates to tryptamine derivatives that are 5-HT₂ agonists forthe treatment of portal hypertension and migraine. U.S. Pat. No.5,874,477 relates to a method for treating malaria using 5-HT_(2A/2C)agonists. U.S. Pat. No. 5,902,815 relates to the use of 5-HT_(2A)agonists to prevent adverse effects of NMDA receptor hypo-function. WO98/31354 relates to 5-HT_(2B) agonists for the treatment of depressionand other CNS conditions. WO 00/12475 relates to indoline derivativesand WO 00/12510 and WO 00/44753 relate to certain indole derivatives as5-HT_(2B) and 5-HT_(2C) receptor agonists for the treatment of a varietyof disorders of the central nervous system, but especially for thetreatment of obesity. WO 00/35922 relates to certainpyrazino[1,2-a]quinoxaline derivatives as 5-HT_(2C) agonists for thetreatment of obsessive compulsive disorder, depression, eatingdisorders, and other disorders involving the CNS. WO 00/77002 and WO00/77010 relate to certain substituted tetracyclic pyrido[4,3-b]indolesas 5-HT_(2C) agonists with utility for the treatment of central nervoussystem disorders including obesity, anxiety, depression, sleepdisorders, cephalic pain, and social phobias among others. Agonistresponse at the 5-HT_(2A) receptor is reported to be the primaryactivity responsible for hallucinogenic activity, with some lesserinvolvement of the 5-HT_(2A) receptor possible [Psychopharmacology, Vol.121:357, 1995].

Certain β-hydroxy or alkoxy 2,5-methoxyphenylalkylamines have beenprepared. β-Hydroxy (2,5-dimethoxyphenyl)propylamine has been preparedas an intermediate in the synthesis of radio-labeled methoxamine, analpha adrenergic agonist [DeMarinis, et al., J. Labelled CompoundRadiopharm., Vol. 9(2):267-70, 1982]. β-Hydroxy(2,5-dimethoxyphenyl)phenethyl methylamine has been prepared and used asa synthetic intermediate in the synthesis of hypolipidemic andhypoglycemic agents [Barfknecht, et al., Journal of Medicinal Chemistry,Vol. 17(3):308-312, 1974]. Other compounds have been prepared andstudied for their CNS activity. β-hydroxy-2,5-dimethoxy amphetamineanalogs were prepared and suggested to have hallucinogenic and/orsympathomimetic activity [Beng, et al., Journal of Medicinal Chemistry,Vol. 13(5):1022, 1970]. A series of β-methoxy phenyethylamine analogshave been prepared and evaluated for their psychotomimetic activity[Lemaire, et al., Journal Pharm. Pharmacol., Vol. 37(8):575-577, 1985].A similar series of 4-substituted β-methoxy 2,5-dimethoxyphenyethylamineanalogs has been prepared [Torres, et al., Synthetic Communications,Vol. 25(8):1239-1247, 1995] and evaluated for serotonergic andadrenergic activity [Torres, et al., Gen. Pharmac., Vol. 31(1):51-54,1998]. The biological activity data derived from studies with many ofthese compounds has been used to generate structure activityrelationships for hallucinogenic phenalkylamines [Beuerle, et al.,Quantitative Structure Activity Relationships, Vol. 16(6):447-458, 1997and Clare, B. W., J. Med. Chem., Vol. 41(20):3845-3856, 1998].

All the patents and publications mentioned above and throughout areherein incorporated in their entirety by reference.

Accordingly, there is a need to provide new compounds which avoid thedisadvantages described above and which provide increased chemicalstability and a desired length of therapeutic activity, for instance, indecreasing intraocular pressure and treating glaucoma. In addition,there is a need to provide improved method of lowering and/orcontrolling elevated intraocular pressure (IPO).

SUMMARY OF THE PRESENT INVENTION

A feature of the present invention is to provide novel compounds whichare 5-HT₂ agonists.

Another feature of the present invention is to provide compounds whichhave increased chemical stability and which are useful in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

Another feature of the present invention is to provide compounds whichhave less CNS activity than other known 5-HT₂ agonists.

Another feature of the present invention is to provide compounds whichprovide a desired level of therapeutic activity in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

To achieve these and other advantages, and in accordance with thepurposes of the present invention, as embodied and broadly describedherein, the present invention relates to a compound having the FormulaI:

Wherein:

-   X=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵;-   Y¹=OH, OR¹, F, OCON(R⁵, R⁶), or OCOR⁵;-   Y²=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵, with the proviso that both Y¹    and Y² are not OH;-   R¹=C₁₋₃ alkyl;-   R²=C₁₋₃ alkyl, Cl, Br, I CF₃, or OR¹;-   R³, R⁴=H, C₁₋₃ alkyl;-   R⁵=C₁₋₆ alkyl; and-   R⁶=H, C₁₋₆ alkyl.    Preferred compounds for lowering and maintaining IOP or treating    glaucoma include compounds wherein:-   R¹=methyl;-   R²=Br, C₁₋₃ alkyl;-   R³, R⁴=H;-   Y¹=methoxy;-   Y²=OH, methoxy; and-   the α and β carbons are in the R configuration.    Novel compounds of the present invention include those defined as    follows:-   X=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵;-   Y¹=OH, OR¹, F, OCON(R⁵, R⁶), or OCOR⁵;-   Y²=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵, with the proviso that both Y¹    and Y² are not OH;-   R¹=C₁₋₃ alkyl;-   R²=C₁₋₃ alkyl, Cl, Br, or I with the proviso that when X=OH, R² is    not I or methyl; and-   R³, R⁴=H, C₁₋₃ alkyl;-   R⁵=C₁₋₆ alkyl; and-   R⁶=H, C₁₋₆ alkyl.    Preferred novel compounds are those wherein:-   R¹=methyl;-   R²=Br, C₁₋₃ alkyl; and-   R³, R⁴=H.    Most preferred novel compounds are those wherein:-   R¹=methyl;-   R²=Br, C₁₋₃ alkyl;-   R³, R⁴=H;-   Y¹=methoxy;-   Y²=OH, methoxy; and-   the α and β carbons are in the R configuration.

The present invention further relates to methods to lower and/or controlnormal or elevated intraocular pressure by administering an effectiveamount of a composition containing a compound having Formula I asdescribed above.

The present invention also relates to a method for treating glaucomawhich involves administering an effective amount of a compositioncontaining a compound having Formula I as described above.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are intended to provide a further explanation of the presentinvention, as claimed.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a variety of compounds which are usefulaccording to the present invention. These compounds are generallyrepresented by the following Formula I.

Wherein:

-   X=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵;-   Y¹=OH, OR¹, F, OCON(R⁵, R⁶), or OCOR⁵;-   Y²=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵, with the proviso that both Y¹    and Y² are not OH;-   R¹=C₁₋₃ alkyl;-   R²=C₁₋₃ alkyl, Cl, Br, I, CF₃, or OR¹;-   R³, R⁴=H, C₁₋₃ alkyl;-   R⁵=C₁₋₆ alkyl; and-   R⁶=H, C₁₋₆ alkyl.    Preferred compounds for lowering and maintaining IOP or treating    glaucoma include compounds wherein:-   R¹=methyl;-   R²=Br, C₁₋₂ alkyl;-   R³, R⁴=H;-   Y¹=methoxy;-   Y²=OH, methoxy; and-   the α and β carbons are in the R configuration.    Novel compounds of the present invention include those defined as    follows:-   X=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵;-   Y¹=OH, OR¹, F, OCON(R⁵, R⁶), or OCOR⁵;-   Y²=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵, with the proviso that both Y¹and    Y² are not OH;-   R¹=C₁₋₃ alkyl;-   R²=C₁₋₃ alkyl, Cl, Br, or I with the proviso that when X=OH, R² is    not I or methyl; and-   R³, R⁴=H, C₁₋₃ alkyl;-   R⁵=C₁₋₆ alkyl; and-   R⁶=H, C₁₋₆ alkyl.    Preferred novel compounds are those wherein:-   R¹=methyl;-   R²=Br, C₁₋₃ alkyl; and-   R³, R⁴=H.    Most preferred novel compounds are those wherein:-   R¹=methyl;-   R²=Br, C₁₋₃ alkyl;-   R³, R⁴=H;-   Y¹=methoxy;-   Y²=OH, methoxy, and-   the α and β carbons are in the R configuration.

Certain compounds of Formula I can contain one or more chiral centers.The present invention contemplates all enantiomers, diastereomers, andmixtures thereof, together with pharmaceutically acceptable saltsthereof.

In the above definitions, the total number of carbon atoms in asubstituent group is indicated by the C_(i-j) prefix where the numbers iand j define the number of carbon atoms. This definition includesstraight chain, branched chain, and cyclic alkyl or (cyclic alkyl) alkylgroups.

In the formulas described above, the alkyl group can be straight-chain,branched or cyclic and the like.

The compounds of the present invention preferably function as 5-HT₂agonists and preferably do not enter the CNS. Compounds having theability to be a 5-HT₂ agonist are beneficial for controlling IOP as wellas the treatment of glaucoma as shown in International Published PatentApplication No. WO/16761, incorporated in its entirety by referenceherein.

The compounds of the present invention preferably provide increasedchemical stability and preferably achieve the desired level oftherapeutic activity which includes a lowering or controlling of IOP.

The compounds of the present invention can be prepared using thetechniques shown in the below set forth reaction schemes and Examples.

The compounds of the present invention can be used to lower and controlIOP, including the IOP associated with normotension glaucoma, ocularhypertension, and glaucoma in mammals including humans. The compoundsare preferably formulated in pharmaceutical compositions which arepreferably suitable for topical delivery to the eye of the patient.

The compounds of this invention, Formula L can be incorporated intovarious types of ophthalmic formulations for delivery to the eye (e.g.,topically, intracamerally, or via an implant). The compounds arepreferably incorporated into topical ophthalmic formulations fordelivery to the eye. The compounds may be combined withophthalmologically acceptable preservatives, viscosity enhancers,penetration enhancers, buffers, sodium chloride, and water to form anaqueous, sterile ophthalmic suspension or solution. Ophthalmic solutionformulations may be prepared by dissolving a compound in aphysiologically acceptable isotonic aqueous buffer. Further, theophthalmic solution may include an ophthalmologically acceptablesurfactant to assist in dissolving the compound. Furthermore, theophthalmic solution may contain an agent to increase viscosity, such ashydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to, gellan and xanthan gum. In order to prepare sterileophthalmic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the active ingredient in a hydrophilic baseprepared from the combination of, for example, carbopol-974, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

The compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 5 to 8. The compounds willnormally be contained in these formulations in an amount 0.01% to 5% byweight, but preferably in an amount of 0.25% to 2% by weight. Thus, fortopical presentation 1 to 2 drops of these formulations would bedelivered to the surface of the eye 1 to 4 times per day according tothe discretion of a skilled clinician.

The compounds can also be used in combination with other agents forlowering IPO and treating glaucoma, such as, but not limited to,β-blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol,levobunolol, propranolol), carbonic anhydrase inhibitors (e.g.,brinzolamide and dorzolamide), α1 antagonists (e.g., nipradolol), α2agonists (e.g. iopidine and brimonidine), miotics (e.g., pilocarpine andepinephrine), prostaglandin analogs (e.g., latanoprost, travoprost,unoprostone, and compounds set forth in U.S. Pat. Nos. 5,889,052;5,296,504; 5,422,368; and 5,151,444, “hypotensive lipids” (e.g.,bimatoprost and compounds set forth in U.S. Pat. No. 5,352,708), andneuroprotectants (e.g., compounds from U.S. Pat. No. 4,690,931,particularly eliprodil and R-eliprodil, as set forth in a pendingapplication U.S. Ser. No. 06/203,350, and appropriate compounds fromWO94/13275, including memantine. Such use in combination may be effectedthrough concurrent or adjunctive administration, or throughadministration of a single composition comprising a combination of acompound of the present invention with one or more of the foregoingadditional agents.

The following methods and examples are given to illustrate thepreparation and effectiveness of compounds that are the subject of thepresent invention, but should not be construed as implying limitationsto the claims.

METHOD 1 5-HT₂ Receptor Binding Assay

To determine the affinities of serotonergic compounds at the 5-HT₂receptors, their ability to compete for the binding of the agonistradioligand [¹²⁵I]DOI to brain 5-HT₂ receptors is determined asdescribed below with minor modification of the literature procedure[Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat cortexhomogenates (400 μl) dispersed in 50 mM TrisHCl buffer (pH 7.4) areincubated with [¹²⁵I]DOI (80 pM final) in the absence or presence ofmethiothepin (10 μM final) to define total and non-specific binding,respectively, in a total volume of 0.5 ml. The assay mixture isincubated for 1 hour at 23° C. in polypropylene tubes and the assaysterminated by rapid vacuum filtration over Whatman GF/B glass fiberfilters previously soaked in 0.3% polyethyleneimine using ice-coldbuffer. Test compounds (at different concentrations) are substituted formethiothepin. Filter-bound radioactivity is determined by scintillationspectrometry on a beta counter. The data are analyzed using anon-linear, iterative curve-fitting computer program [Trends Pharmacol.Sci., 16, 413 (1995)] to determine the compound affinity parameter. Theconcentration of the compound needed to inhibit the [¹²⁵ I]DOI bindingby 50% of the maximum is termed the IC₅₀.

METHOD 2 5-HT₂ Functional Assay: Phosphoinositide (PI) Turnover Assay

The relative agonist activity of serotonergic compounds at the 5-HT₂receptor can be determined in vitro using the ability of the compoundsto stimulate the production of [³H]inositol phosphates in[³H]myo-inositol-labeled A7r5 rat vascular smooth muscle cells by theirability to activate the enzyme phospholipase C. These cells are grown inculture plates, maintained in a humidified atmosphere of 5% CO₂ and 95%air and fed semi-weekly with Dulbecco's modified Eagle medium (DMEM)containing 4.5 g/L glucose and supplemented with 2 mM glutamine, 10μg/ml gentamicin, and 10% fetal bovine serum. For the purpose ofconducting the phosphoinositide (PI) turnover experiments, the A7r5cells are cultured in 24-well plates as previously [J. Pharmacol. Expt.Ther. 286, 411 (1998)]. Confluent cells are exposed for 24-30 hrs to 1.5μCi [³H]-myo-inositol (18.3 Ci/mmol) in 0.5 ml of serum-free medium.Cells are then rinsed once with DMEM/F-12 containing 10 mM LiCl prior toincubation with the test agent (or solvent as the control) in 1.0 mL ofthe same medium for 1 hr at 37° C., after which the medium is aspiratedand 1 ml of cold 0.1 M formic acid added to stop the reaction. Thechromatographic separation of [³H]-inositol phosphates ([³H]-IPs) on anAG-1-X8 column is performed as previously described [J. Pharmacol. Expt.Ther. 286, 411 (1998)] with sequential washes with H₂O and 50 mMammonium formate, followed by elution of the total [³H]-IPs fractionwith 1.2 M ammonium formate containing 0.1 M formic acid. The eluate (4mL) is collected, mixed with 15 ml scintillation fluid, and the total[³H]-IPs determined by scintillation counting on a beta-counter.Concentration-response data are analyzed by the sigmoidal fit functionof the Origin Scientific Graphics software (Microcal Software,Northampton, Mass.) to determine agonist potency (EC₅₀ value) andefficacy (Emax). Serotonin (5-HT) is used as a positive control(standard) agonist compound and the efficacy of test compounds iscompared to that of 5-HT (set at 100%). The concentration of thecompound needed to stimulate the production of [³H]-IPs by 50% of themaximum response is termed the EC₅₀ value.

METHOD 3 5-HT₂ Functional Assay: [Ca²⁺]_(i) Mobilization

The receptor-mediated mobilization on intracellular calcium ([Ca²⁺]_(i))was studied using the Fluorescence Imaging Plate Reader (FLIPR)instrument. Rat vascular smooth muscle cells, A7r5, were grown in anormal media of DMEM/10% FBS and 10 μg/mL gentamycin. Confluent cellmonolayers were trypsinized, pelleted, and re-suspended in normal media.Cells were seeded in a 50 μL volume at a density of 20,000 cells/well ina black wall, 96-well tissue culture plate and grown for 2 days.

On the day of the experiment, one vial of FLIPR Calcium Assay Kit dyewas re-suspended in 50 mL of a FLIPR buffer consisting of Hank'sBalanced Salt Solution (HBSS), 20 mM HEPES, and 2.5 mM probenecid, pH7.4. Cells were loaded with the calcium-sensitive dye by addition of anequal volume (50 μL) to each well of the 96-well plate and incubatedwith dye for 1 h at 23° C.

Typically, test compounds were stored at 25 μM in 50% DMSO/50% Ethanolsolvent. Compounds were diluted 1:50 in 20% DMSO/20% Ethanol. For “hit”screening, compounds were further diluted 1:10 in FLIPR buffer andtested at a final concentration of 10 μM. For dose-response experiments,compounds were diluted 1:50 in FLIPR buffer and serially diluted 1:10 togive a 5- or 8-point dose-response curve.

The compound plate and cell plate were placed in the FLIPR instrument.At the beginning of an experimental run, a signal test was performed tocheck the basal fluorescence signal from the dye-loaded cells and theuniformity of the signal across the plate. The basal fluorescence wasadjusted between 8000-12000 counts by modifying the exposure time, thecamera F-stop, or the laser power. Instrument settings for a typicalassay were the following: laser power 0.3-0.6 W, camera F-stop F/2, andexposure time 0.4 sec. An aliquot (25 μL) of the test compound was addedto the existing 100 μL dye-loaded cells at a dispensing speed of 50μL/sec. Fluorescence data were collected in real-time at 1.0 secintervals for the first 60 secs and at 6.0 sec intervals for anadditional 120 secs. Responses were measured as peak fluorescenceintensity minus basal and where appropriate were expressed as apercentage of a maximum 5-HT-induced response.

The above procedures were used to generate the data shown in Table 1.TABLE I 5-HT₂ Binding 5-HT_(2A) EC₅₀ 5-HT_(2A) 5-HT_(2A) 5-HT_(2A)(IC₅₀) nM nM % Emax EC₅₀ nM % E_(max) Comp. Structure Common Name (PIAssay) (PI Assay) (Ca⁺² Assay) (Ca⁺² Assay) 1

>1,000   9% 2

15,000  1.2% 3

>1,000  1.9% 4

1 17.5 51.0% 5

6.8  3.1% 6

5.9  7.8% 7

57  4.8% 8

26 8000 57%   20% 9

3.2 1180 68% 84   22% 10

2.9 47%   16% 11

1.4 1130 102% 96.9   54% 12

2.2 1080 100% 1330   54% 13

48.9 4610 117% 5040   49% 14

0.74 42.4 111% 126   93% 15

1.7 1410   31%

Table 1 reports the 5-HT2 receptor affinity and function activity of aseries of reference compounds (compounds 1-7) and examples of thecompounds of this invention (8-15). Examples 8-15 have both highaffinity for the 5-HT₂ receptor (IC₅₀<100 nM) and are functionalagonists (% E_(max)>20%). The compounds of this invention are similar inpotency to known 5-HT₂ agonist DOB (4).

METHOD 4 Intraocular Pressure Response in Lasered Monkeys

Intraocular pressure (IOP) was determined with an Alcon Pneumatonometerafter light corneal anesthesia with 0.1% proparacaine. Eyes were washedwith saline after each measurement. After a baseline IOP measurement,test compound was instilled in one 30 μL aliquot to the right eyes onlyof nine cynomolgus monkeys. Vehicle was instilled in the right eyes ofsix additional animals on the same schedule. IOP measurements were takenat 1, 3, and 6 hours after dosing.

Compound 9, a 5-HT₂ agonist, significantly lowered IOP in the laseredmonkey eye by 10.7% (3.0 mmHg), 19% (7 mmHg) and 22.1% (8.1 mmHg) at 1,3, and 6 hours, respectively in lasered monkeys after a single topicalocular instillation of 300 μg (Pharmacology Study No. 16744).

A single 300 μg topical ocular instillation compound 11 a serotonin5-HT₂ agonist, lowered IOP in the lasered monkey eye by 19% (8 mmHg),27.5% (11 mmHg), and 25.5% (10 mmHg) at 1, 3, and 6 hours, respectively(Pharmacology Study No. 16775).

Synthesis of Compounds 9 and 8 from Table 1

Compound 9 and Compound 8 were prepared from Compound A and Compound B,respectively, which are identified and discussed below. The chiralpurity of Compounds A and B were established by examination of the NMRspectra in the presence of the chiral shift reagent, Eu(hfbc) [McClure,D. E.; Arison, B. H.; Baldwin, J. J. Mode of nucleophilic addition ofepichlorohydrin and related species: chiral aryloxymethyloxiranes. J.Am. Chem. Soc. 1979, 101, 3666-3668]. Chiral shift NMR analysis revealednone of the opposite enantiomer, indicating a chiral purity of>98 % foreach isomer.

(S)-(−)-2-[N-(Trifluoroacetyl)amino]-1-(2,5-dimethoxy-4-bromophenyl)-1-propanone(Compound A). Oxalyl chloride (11.64 g, 91.8 mmol) was added in oneportion to a stirred mixture of N-(trifluoroacetyl)-L-alanine [Weygand,F.; Leising, E. N-Trifluoracetylaminosäuren. II. Mitteil. Chem. Ber.1954, 87, 248-256] (8.00 g, 43.2 mmol) and dry pyridine (0.5 mL) in dryCH₂Cl₂ (300 mL) at 0° C. under an N₂ atmosphere. The reaction mixturewas allowed to warm to room temperature and to stir for an additional 2h. The mixture was concentrated under reduced pressure at a temperaturebelow 30° C. to give an oil which was mixed with1-bromo-2,5-dimethoxybenzene (9.38 g, 43.2 mmol). The resulting mixturewas dissolved in dry CH₂Cl₂ (25 mL) and added dropwise to a stirredsolution of 1M TiCl₄ in CH₂Cl₂ (64.8 m L) at −50° C. under an N₂atmosphere. The reaction mixture was allowed to warm to room temperatureand to stir for an additional 60 h. After the reaction was complete, thereaction mixture was poured onto crushed ice. The organic portion wasseparated and washed successively with 1M HCl (2×50 ml), H₂O (2×50 mL),and saturated NaHCO₃ solution (2×50 mL). The solution was dried (MgSO₄)and evaporated to dryness under reduced pressure to give a crude brownproduct. The product was purified by flash chromatography (silica gel;CH₂Cl₂) and recrystallized from Et₂O/hexanes to yield 5.97 g (36%) ofCompound A as a white solid: mp 144-145° C.; [a]_(D)=−28.9° (c 1, MeOH);¹H NMR (CDCl₃) d 1.43 (d, J=6.2 Hz, 3H, CH₃), 3.90 (s, 3H, OCH₃), 3.95(s, 3H, OCH₃), 5.59 (m, 1H, CH), 7.26 (s, 1H, ArH), 7.41 (s, 1H, ArH),7.61. (bs, 1H, NHCO, exchangeable).

(R)-(+)-2-[N-(Trifluoroacetyl)amino]-1-(2,5-dimethoxy-4-bromophenyl)-1-propanone(Compound B). An exact replication of the above procedure usingN-(trifluoroacetyl)-D-alanine [Fones, W. S. Some new N-acyl derivativesof alanine and phenylalanine. J. Org. Chem. 1952, 17, 1661-1665] gave6.30 g (38%) of Compound B as a white crystals: mp 144-145° C.;[a]_(D)=+28.4° (c 1, MeOH).

Erythro isomers Compound 9 and Compound 8 were prepared by a highlyerythro-selective reduction [Fujita, M.; Hiyama, T. Erythro-directivereduction of a-substituted alkanones by means of hydrosilanes in acidicmedia. J. Org. Chem. 1988, 53, 5415-5421] of the corresponding ketonesCompound A and Compound B with dimethylphenylsilane in TFA.

(−)-erythro-(1R,2S)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydro-chloride (Compound 9). Dimethylphenylsilane (1.70 g, 12.5 mmol)was added in dropwise manner to a solution of(S)-(−)-2-[N-(trifluoroacetyl)amino]-1-(2,5-dimethoxy-4-bromophenyl)-1-propanone(Compound A) (3.84 g, 10.0 mmol) in TFA (5 ml) at −5° C. under a N₂atmosphere. The reaction mixture was allowed to warm to 0° C. andstirred for an additional 2 h. After the reaction was complete, thereaction mixture was poured onto crushed ice and neutralized withsaturated NaHCO₃ solution. The solution was extracted with CH₂Cl₂ (3×50mL). The combined CH₂Cl₂ portions were washed with saturated NaHCO₃solution (3×25 mL), brine (3×25 mL), dried (MgSO₄) and evaporated todryness under reduced pressure. The resulting residue was purified byflash chromatography with silica gel using, sequentially, CH₂Cl₂ andMeOH/CH₂Cl₂ (1:20) as eluants, and then dissolved in MeOH (30 ml). Thesolution was added to a stirred mixture of K₂CO₃ (6.91 g, 50 mmol) inH₂O (5 mL) and then heated at reflux for 2 h. MeOH was removed underreduced pressure and the residue was extracted with CH₂Cl₂ (3×25 mL).The combined organic portions were dried (MgSO₄), and the solvent wasevaporated under reduced pressure to give the crude free base ofCompound 9 as a white/yellowish solid. The free base was dissolved inanhydrous Et₂O (50 mL) and treated with ethereal HCl. The precipitatedHCl salt was collected by filtration, washed with anhydrous Et₂O (2×10mL), and recrystallized from EtOAc to afford 2.28 g (70%) of ALC-354 asa white crystals: mp 197-199° C.; [a]_(D)=−37.1° (c 1, MeOH); ¹H NMR(DMSO-d₆) d 0.92 (d, J=6.7 Hz, 3H, CH₃), 3.38 (m, 1H, CH—NH₃ ⁺), 3.76(s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 5.06 (m, 1H, CH—OH), 6.06 (d, J=3.3Hz, 1H, OH, exchangeable), 7.14 (s, 1H, ArH), 7.23 (s, 1H, ArH), 8.04(br.s, 3H, NH₃ ⁺, exchangeable). Anal. (C₁₁H₁₆BrNO₃×HCl) C, H, N.

(+)-erythro-(1S,2R)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride (ALC-355) was prepared from(R)-(+)-2-[N-(Trifluoroacetyl)amino]-1-(2,5-dimethoxy-4-bromophenyl)-1-propanone(Compound B) as a white crystals in 68% yield as described for Compound9: mp 194-196° C.; [a]_(D)=+42.9° (c 1, MeOH); Anal.(C₁₁H₁₆BrNO₃×HCl×0.5H₂O) C, H, N.

Synthesis of Compound 10 and Compound 11

Threo isomers Compounds 10 and 11 were prepared from the correspondingerythro compounds 9 and 8 using a modification of a procedure that waspreviously described for the preparation of threo norpseudoephedrines[Brauch, F.; Dralle, H.; Blanke, H. J. Ger. Offen. DE 3,408,850, Sep.13, 1984; Chem. Abstr. 1985, 102, 24270p].

(+)-threo-(1S,2S)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride (Compound 10). Acetic anhydride (3.57 g, 35.0 mmol) wasadded to the free base of(−)-erythro-(1R,2S)-1-hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane(2.90 g, 10.0 mmol) (Compound 9) at room temperature under a N₂atmosphere. The reaction mixture was heated at 110° C. for 1 h and thencooled to 60-80° C. A solution of 60% aqueous H₂SO₄ (8 mL) was added andthe reaction mixture was heated at 110° C. for an additional 1 h. Themixture was cooled to room temperature, poured onto crushed ice andbasified with 15% aqueous NaOH solution until pH=8. The solution wasextracted with CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ portions werewashed with brine (3×50 mL), dried (MgSO₄) and evaporated under reducedpressure. The resulting residue was purified by flash chromatography(silica gel; CH₂Cl₂/MeOH (4:1)) to give an oil. The oil was dissolved inanhydrous Et₂O (50 mL) and treated with ethereal HCl. The precipitatedHCl salt was collected by filtration, washed with anhydrous Et₂O (2×10mL), and then recrystallized from Et₂O/MeOH to afford 2.67 g (82%) ofCompound 10 as white crystals: mp 213-214° C.; [a]_(D)=+30.9° (c 1,MeOH); ¹H NMR (DMSO-d₆) d 1.03 (d, J=6.7 Hz, 3H, CH₃), 3.27 (m, 1H,CH—NH₃ ⁺), 3.76 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 4.84 (m, 1H, CH—OH),6.16 (d, J=3.3 Hz, 1H, OH, exchangeable), 7.14 (s, 1H, ArH), 7.25 (s,1H, ArH), 7.98 (br.s, 3H, NH₃ ⁺, exchangeable). Anal. (C₁₁H₁₆BrNO₃×HCl)C, H, N.

(−)-threo-(1R,2R)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride (Compound 11) was prepared from(+)-erythro-(1S,2R)-1-hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane(Compound 8) as white crystals in 80% yield as described for Compound10: mp 214-215° C.; [a]_(D)=−31.3° (c 1, MeOH); Anal. (C₁₁H₁₆BrNO₃×HCl)C, H, N.

Synthesis of Compound 12 and Compound 13

(−)-erythro-(1R,2S)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate (Compound 12). A solution of(−)-erythro-(1R,2S)-1-hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane(free base of Compound 9) (2.90 g, 10.0 mmol) in THF (10 mL) was addedin a dropwise manner to a suspension of 95% NaH (0.38 g, 15.0 mmol) inTHF (5 mL) at 0° C. under a N₂ atmosphere. After stirring at roomtemperature for 0.5 h, the reaction mixture was treated in a dropwisemanner with CH₃I (1.42 g, 10.0 mmol) at 0° C. and then heated at refluxfor 1 h. The mixture was allowed to cool to room temperature, and thenMeOH (3 mL) was added to destroy any excess NaH. The solution wasconcentrated under reduced pressure and diluted with H₂O (10 mL). Theresulting mixture was extracted with CH₂Cl₂ (3×25 mL). The combinedCH₂Cl₂ portions were washed with brine (3×25 mL), dried (MgSO₄) andevaporated under reduced pressure to give a crude oil. The oil waspurified by flash chromatography (silica gel; CH₂Cl₂/MeOH, 9:1),dissolved in anhydrous Et₂O (50 mL), and treated with ethereal oxalicacid. The precipitated oxalate salt was collected by filtration, washedwith anhydrous Et₂O (2×10 mL), and recrystallized from Et₂O/MeOH toafford 2.88 g (73%) of Compound 12 as a white crystals: mp 186-188° C.;[a]_(D)=−59.8° (c 1, MeOH); ¹H NMR (DMSO-d₆) d 0.95 (d, J=6.8 Hz, 3H,CH₃), 3.27 (s, 3H, CH—OCH ₃) 3.40 (m, 1H, CH—NH₃ ⁺), 3.78 (s, 3H, OCH₃),3.81 (s, 3H, OCH₃), 4.75 (d, J=2.8 Hz, 1H, CH—OCH₃), 6.91 (s, 1H, ArH),7.30 (s, 1H, ArH). Anal. (C₁₂H₁₈BrNO₃×C₂H₂O₄) C, H, N.

(+)-erythro-(1S,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate (Compound 13) was prepared from(+)-erythro-(1S,2R)-1-hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane(free base of Compound 8) as a white crystals in 67% yield as describedfor Compound 12: mp 189-192° C.; [a]_(D)=+58.2° (c 1, MeOH); Anal.(C₁₁H₁₆BrNO₃×C₂H₂O₄) C, H, N.

Synthesis of Compound 15 and Compound 14

(+)threo-(1S,2S)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate (Compound 15) was prepared from (+)-threo-(1S,2S)-1-hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (Compound10) as a white crystals in 52% yield as described for ALC-361: mp115-118° C.; [a]_(D)=+51.7° (c 1, MeOH); ¹H NMR (DMSO-d₆) d 0.96 (d,J=6.7 Hz, 3H, CH₃), 3.14 (s, 3H, CH—OCH ₃) 3.40 (m, 1H, CH—NH₃ ⁺), 3.78(s, 3H, OCH₃), 3.81 (s, 3H, OCH₃), 4.55 (d, J=8.7 Hz, 1H, CH—OCH₃), 6.96(s, 1H, ArH), 7.32 (s, 1H, ArH). Anal. (C₁₁H₁₆BrNO₃×C₂H₂O₄) C, H, N.

(−)-thero-(1R,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate (Compound 14) was prepared from(−)-threo-(1R,2R)-1-hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane(Compound 11) as a white crystals in 73% yield as described for Compound12: mp 115-118° C.; [a]_(D)=−52.2° (c 1, MeOH); Anal.(C₁₁H₁₆BrNO₃×C₂H₂O₄) C, H, N.

Synthesis of Compound 5

(±)1-Hydroxy-1-[4-(3-phenylpropyl)-2,5-dimethoxyphenyl]-2-aminoethaneHydrochloride (Compound 5). SnCl₄ (3.25 g, 12.5 mmol) was added in adropwise manner to a solution of 1,4-dimethoxy-2-(3-phenylpropyl)benzene[Asano, M.; Aihara, T.; Aiko, I., Hasegawa, H. Syntheses of aryl- andaralkyl dihydroxybenzoquinones. Yakugaku Zasshi 1943, 63, 686-690; Chem.Abstr. 1952, 46, 93i] (2.56 g, 10.0 mmol) and Cl₂CHOCH₃ (1.15 g, 10.0mmol) in CH₂Cl₂ (25 mL) at −10° C. under an N₂ atmosphere. After theaddition was complete, the reaction mixture was allowed to warm to roomtemperature and stirred for an additional 2 h. The mixture was pouredonto crushed ice. The organic portion was separated and washed with H₂O(2×100 mL), saturated NaHCO₃ solution (2×100 mL) and again with H₂O(2×100 mL). The solution was dried (MgSO₄) and evaporated under reducedpressure to give a yellow oil. The oil was dissolved in Et₂O (8 mL) andtreated with saturated NaHSO₃ solution (50 mL). The resulting mixturewas vigorously stirred for 12 h. The white precipitate was collected byfiltration and washed with Et₂O (3×25 mL). The solid was suspended insaturated Na₂CO₃ solution (50 mL) and allowed to stir for 1 h. Themixture was extracted with CH₂Cl₂ (3×75 mL). The combined CH₂Cl₂portions were washed with H₂O (3×50 mL), dried (MgSO₄), and evaporatedunder reduced pressure to give 2.55 g (90%) of1-hydroxy-1-[4-(3-phenylpropyl)-2,5-dimethoxyphenyl]benzaldehyde asyellowish oil: ¹H NMR (CDCl₃) d 1.95 (m, 2H, CH₂), 2.68 (m, 4H, CH₂),3.83 (s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 6.78 (s, 2H, ArH), 7.27 (m, 5H,ArH), 10.41 (s, 1H, CHO).

Nirtomethane (0.61 g, 10.0 mmol) was added in a dropwise manner to asolution of1-hydroxy-1-[4-(3-phenylpropyl)-2,5-dimethoxyphenyl]benzaldehyde (2.84g, 10.0 mmol) and CH₃ONa (0.67 g, 12.5 mmol) in MeOH (5 mL) at 0° C.under an N₂ atmosphere. After stirring at 0-5° C. for 2 h, the reactionmixture was treated with Et₂O (50 mL). The yellowish precipitate wascollected by filtration and suspended in Et₂O (50 mL). Glacial AcOH(0.75 g, 12.5 mmol) was added and the white precipitate was removed byfiltration. The filtrate was washed with H₂O (3×50 mL), dried (MgSO₄),and evaporated to dryness under reduced pressure to give 2.59 g (75%) ofthe crude1-hydroxy-1-[4-(3-phenylpropyl)-2,5-dimethoxyphenyl]-2-nitroethane as apale yellow solid. The product was used in the next step without anyadditional purification and characterization. PtO₂ (0.10 g, 0.4 mmol)was added to a solution of the solid (2.59 g, 7.5 mmol) in MeOH (50 mL)in a Parr bottle. This mixture was shaken at 50 psig of H₂ for 48 h. Thecatalyst was removed by filtration through a Celite pad and the filtratewas evaporated under reduced pressure to give a crude product.Purification by flash chromatography (silica gel; CH₂Cl₂/MeOH, 4:1)afforded the pure free base of Compound 5 as a white solid: mp 111-112°C. The solid was dissolved in anhydrous Et₂O (80 mL) and treated withethereal HCl. The precipitated hydrochloride salt was collected byfiltration, washed with anhydrous Et₂O (2×10 mL), and recrystallizedfrom Et₂O/MeOH to afford 1.69 g (64%) of Compound 5 as a white crystals:mp 174-176° C.; ¹H NMR (DMSO-d₆) d 1.83 (m, 2H, CH₂), 2.58 (m, 4H, CH₂),2.73 (m, 1H, CH₂), 2.96 (m, 1H, CH₂), 3.73 (s, 3H, OCH₃), 3.75 (s, 3H,OCH₃) 5.05 (m, 1H, CH—OH), 5.89 (d, J=4.1 Hz, 1H, OH, exchangeable),6.81 (s, 1H, ArH), 7.04. (s, 1H, ArH),), 7.24 (s, 5H, ArH), 7.96 (br.s,3H, NH₃ ⁺, exchangeable). Anal. (C₁₉H₂₅NO₃×HCl) C, H, N.

Synthesis of Compound 7

(−)-erythro-(1R,2S)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminobutaneOxalate (Compound 7).(S)-(−)-2-[N-(Trifluoroacetyl)amino]-1-(2,5-dimethoxy-4-bromophenyl)-1-butanone(Compound C) was prepared in 29% yield from(S)-(+)-2-trifluoroacetylaminobutyric acid [Fones, W. S.; Lee, M.Hydrolysis of the N-trifluroacetyl derivatives of several D- and L-aminoacids by acylase I. J. Biol. Chem. 1954, 210, 227-238] exactly asdescribed for the synthesis of Compound A. The product was isolated as ayellow/white powder: mp 92-94° C.; [a]_(D)=−5.7° (c 1, MeOH); ¹H NMR(CDCl₃) d 0.87 (t, J=7.6 Hz, 3H, CH₃), 1.61 (m, 2H, CH₂), 3.93 (s, 3H,OCH₃), 3.97 (s, 3H, OCH₃), 5.58 (m, 1H, CH), 7.28 (s, 1H, ArH), 7.41 (s,1H, ArH), 7.44 (bs, 1H, NHCO, exchangeable). Using this as startingmaterial, Compound 7 was prepared in the same manner described for thesynthesis of Compound 9, except that ethereal oxalic acid was used toisolate the product as the oxalate salt. The salt was recrystallizedfrom MeOH/Et₂O to afford ALC-391 as a white crystals in 76% yield: mp203-205° C.; [a]_(D)=−28.5° (c 1, MeOH); ¹H NMR (DMSO-d₆) d 0.78 (t,J=7.3 Hz, 3H, CH₃), 1.33 (m, 2H, CH₂), 3.19 (m, 1H, CH—NH₃ ⁺), 3.77 (s,3H, OCH₃), 3.80 (s, 3H, OCH₃), 5.10 (m, 1H, CH—OH), 7.17 (s, 1H, ArH),7.23 (s, 1H, ArH). Anal. (C₁₂H₁₈BrNO₃×C₂H₂O₄) C, H, N.

EXAMPLES

The following topical ophthalmic formulations are useful according tothe present invention administered 1-4 times per day according to thediscretion of a skilled clinician.

Example 1

Ingredients Amount (wt %) Compound 9   1% Hydroxypropyl methylcellulose0.5% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5%Disodium EDTA (Edetate disodium) 0.01%  Polysorbate 80 0.05% Benzalkonium chloride 0.01%  Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

Example 2

Ingredients Amount (wt %) Compound 11 0.6% Methyl cellulose 4.0% Dibasicsodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA(Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4Purified water q.s. to 100%

Example 3

Ingredients Amount (wt %) Compound 9 0.6% Guar gum 0.4-6.0%    Dibasicsodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA(Edetate disodium) 0.01%  Polysorbate 80 0.05%  Benzalkonium chloride0.01%  Sodium hydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4Purified water q.s. to 100

Example 4

Ingredients Amount (wt %) Compound 11 0.7% White petrolatum and mineraloil and lanolin Ointment consistency Dibasic sodium phosphate(anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium)0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

1. A method for lowering and controlling intraocular pressure and/ortreating a mammal suffering from glaucoma, which comprises,administering to the mammal a pharmaceutically effective amount of acompound of the following formula I:

wherein: X=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵; Y¹=OH, OR¹, F, OCON(R⁵, R⁶),or OCOR⁵; Y²=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵, with the proviso that bothY¹ and Y² are not OH; R¹=C₁₋₃ alkyl; R²=C₁₋₃ alkyl, Cl, Br, I, CF₃, orOR¹; R³, R⁴=H, C₁₋₃ alkyl; R⁵=C₁₋₆ alkyl; and R⁶=H, C₁₋₆ alkyl; andpharmaceutically acceptable salts thereof.
 2. The method of claim 1,wherein for the compound of formula I: R¹=methyl; R²=Br, C₁₋₃ alkyl; andR³, R⁴=H.
 3. The method of claim 2, wherein for the compound of formulaI; Y¹=methoxy; Y²=OH, methoxy; and the α and β carbons are in the Rconfiguration.
 4. The method of claim 1, wherein the mammal is a humanand the compound is administered topically.
 5. The method of claim 1,which further comprises, administering an intraocular pressure (IOP)lowering effective amount of an IOP lowering agent selected from thegroup consisting of: β-blockers, carbonic anhydrase inhibitors, α2agonists, prostaglandin analogs, and combinations thereof.
 6. The methodof claim 5, wherein the compound of formula I and the IOP lowering agentare administered together as a single composition.
 7. The method ofclaim 1, wherein the compound of formula I is selected from the groupconsisting of:(−)-erythro-(1R,2S)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride;(+)-erythro-(1S,2R)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride; (+)-threo-(1S,2S)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride;(−)-threo-(1R,2R)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride;(−)-erythro-(1R,2S)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate;(+)-erythro-(1S,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate;(+)-threo-(1S,2S)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate;(−)-threo-(1R,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate; and their pharmaceutically acceptable salts.
 8. The method ofclaim 5, wherein the compound of formula I is:(−)-threo-(1R,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate and its pharmaceutically acceptable salts.
 9. A compound of thefollowing formula I:

wherein: X=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵; Y¹=OH, OR¹, F, OCON(R⁵, R⁶),or OCOR⁵; Y²=OH, OR¹, OCON(R⁵, R⁶), or OCOR⁵, with the proviso that bothY¹ and Y² are not OH; R¹=C₁₋₃ alkyl; R²=C₁₋₃ alkyl, Cl, Br, or I withthe proviso that when X=OH, R² is not I or methyl; R³, R⁴=H, C₁₋₃ alkyl;R⁵=C₁₋₆ alkyl; and R⁶=H, C₁₋₆ alky; and pharmaceutically acceptablesalts thereof.
 10. The compound of claim 9, wherein for formula I:R¹=methyl; R²=Br, C₁₋₃ alkyl; and R³, R⁴=H.
 11. The compound of claim10, wherein for formula I: Y¹=methoxy; Y²=OH, methoxy; and the α and βcarbons are in the R configuration.
 12. The compound of claim 9, whichis selected from the group consisting of:(−)-(erythro-(1R,2S)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride;(+)-erythro-(1S,2R)-1-Hydroxy-1-(4-bromo-2,5dimethoxyphenyl)-2-aminopropaneHydrochloride; (+)-threo-(1S,2S)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride;(−)-threo-(1R,2R)-1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneHydrochloride;(−)-erythro-(1R,2S)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate;(+)-erythro-(1S,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate;(+)-threo-(1S,2S)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate;(−)-threo-(1R,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate; and their pharmaceutically acceptable salts.
 13. The compoundof claim 12, which is:(−)-threo-(1R,2R)-1-Methoxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropaneOxalate.